Opioid Abuse in Chronic Pain — Misconceptions and Mitigation Strategies — NEJM – Nora D. Volkow, M.D. [Director of the National Institute on Drug Abuse (NIDA)], and A. Thomas McLellan, Ph.D. – Mar 2016 – free full-text article
Chronic pain not caused by cancer is among the most prevalent and debilitating medical conditions but also among the most controversial and complex to manage.
The urgency of patients’ needs, the demonstrated effectiveness of opioid analgesics for the management of acute pain, and the limited therapeutic alternatives for chronic pain have combined to produce an overreliance on opioid medications in the United States, with associated alarming increases in diversion, overdose, and addiction
Here, we draw on recent research to address common misconceptions regarding the abuse-related risks of opioid analgesics and highlight strategies to minimize those risks.
Given the lack of clinical consensus and research-supported guidance, physicians understandably have questions about whether, when, and how to prescribe opioid analgesics for chronic pain without increasing public health risks.
Source of the Opioid Epidemic
…this review focuses on the pharmacologic properties of opioids that underlie both their therapeutic effects and their abuse-producing effects and on the ways in which these properties should inform us in correcting common clinical misconceptions that interfere with the proper prescription and monitoring of opioids in the management of chronic pain
Table 1. Misconceptions Regarding Opioids and Addiction.
Why Opioid Medications Are Diverted and Abused
Opioid medications exert their analgesic effects predominantly by binding to mu-opioid receptors.
Mu-opioid receptors are densely concentrated in brain regions that regulate pain perception (periaqueductal gray, thalamus, cingulate cortex, and insula), including pain-induced emotional responses (amygdala), and in brain reward regions (ventral tegmental area and nucleus accumbens) that underlie the perception of pleasure and well-being.
This explains why opioid medications can produce both analgesia and euphoria.
Yet people who take opioids when they are in pain do NOT experience euphoria from opioids.
Mu-opioid receptors in other brain regions and in peripheral organs account for other common opioid effects. In particular, mu-opioid receptors in the brain stem are mainly responsible for the respiratory depression associated with opioid-overdose incidents and deaths.
Opioids not only directly activate these brain analgesia and reward regions but also concurrently mediate a learned association between receipt of the drug and the physiological and perceptual effects of the drug — a type of Pavlovian conditioning.
Repeated receipt of opioids strengthens these learned associations and over time becomes part of the desire (craving) for the drug’s effects — analgesic or pleasurable.
For a patient in chronic pain, even mild levels of pain can trigger the learned associations between pain and drug relief, which are manifested as an urge for relief. Such a conditioned urge for relief from even mild pain can lead to the early, inappropriate use of an opioid outside prescribed scheduling.
Here, the desire for pain relief is practically equated with addiction.
The effects of opioids — particularly their rewarding effects — are accentuated most when the drugs are delivered rapidly into the brain. This is why diverted opioids that are taken for their rewarding effects are frequently injected.
My opioid pain medication takes roughly 2 hours to have an effect, so there is NO immediate reward and NO association even with pain relief.
This also explains why the Food and Drug Administration has encouraged and approved abuse-deterrent formulations that are designed to prevent the injection of pharmaceutical opioids
Opioid-Induced Tolerance and Physical Dependence
There is lingering misunderstanding among some physicians about the important differences between physical dependence and addiction.
This is because the DSM-V has created a straight line from physical dependence to the mental dependence of addiction.
The repeated administration of any opioid almost inevitably results in the development of tolerance and physical dependence.
These predictable phenomena reflect counter-adaptations in opioid receptors and their intracellular signaling cascades.
These short-term results of repeated opioid administration resolve rapidly after discontinuation of the opioid (i.e., in a few days to a few weeks, depending on the duration of exposure, type of opioid, and dose).
In contrast, addiction will occur in only a small percentage of patients exposed to opioids.
Coming from the director of the National Institute on Drug Abuse, this statement should carry significant weight against PROP’s fallacious argument that anyone taking opioids regularly is addicted.
Addiction develops slowly, usually only after months of exposure, but once addiction develops, it is a separate, often chronic medical illness that will typically not remit simply with opioid discontinuation and will carry a high risk of relapse for years without proper treatment.
This negates all the hype that just taking a few pills leads to certain addiction and eventually death (if you aren’t spiritually “saved” by a 12-step program, according to 12-step lore that’s been promoted as “the only” effective treatment for addiction).
The molecular processes responsible for addiction are also distinct from those underlying tolerance and physical dependence, and so are the clinical consequences.
Tolerance leads to a decrease in opioid potency with repeated administration. Thus, prescribing opioids long-term for their analgesic effects will typically require increasingly higher doses in order to maintain the initial level of analgesia — up to 10 times the original dose.
Similarly, tolerance with respect to the rewarding effects of opioids leads to the characteristic dose escalation seen in opioid addiction, which can result in daily doses of up to 800 morphine milligram equivalents (MME, the conversion factor used to facilitate comparison of potency among opioids).
Physical dependence underlies the physiological adaptations that are responsible for the emergence of withdrawal symptoms on the abrupt discontinuation of opioids.
Withdrawal symptoms (e.g., piloerection, chills, insomnia, diarrhea, nausea, vomiting, and muscle aches) vary appreciably in severity (from not noticeable to quite uncomfortable) and duration (1 to 14 days) on the basis of the type, dose, and duration of opioid prescribed.
In the context of chronic pain management, the discontinuation of opioids requires dose tapering in order to prevent the emergence of such withdrawal symptoms. In some patients, the repeated use of opioids can also lead to hyperalgesia, which is a state of heightened pain sensitivity.
Hyperalgesia has been proven to exist only in rodents, not humans, so the repeated warnings of this phenomenon only feed propaganda against opioids.
In the clinical context, hyperalgesia can lead to inappropriate increases in opioid doses, which further exacerbate rather than ameliorate pain. In the case of hyperalgesia, dose tapering or tapering to discontinuation is a better pain-relief strategy.
Factors Associated with the Risk of Opioid Overdose or Addiction.
Unlike tolerance and physical dependence, addiction is not a predictable result of opioid prescribing.
Thank you, Dr. Volkow, for stating this unequivocally. This is opposite of what is being reported. The hype insists that taking a single pill can “cause addiction and lead to death”.
Factors Associated with the Risk of Opioid Overdose or Addiction.
Older medical texts and several versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) either overemphasized the role of tolerance and physical dependence in the definition of addiction or equated these processes (DSM-III and DSM-IV).
However, more recent studies have shown that the molecular mechanisms underlying addiction are distinct from those responsible for tolerance and physical dependence, in that they evolve much more slowly, last much longer, and disrupt multiple brain processes.
Cardinal features of addiction include
- a pronounced craving for the drug,
- obsessive thinking about the drug,
- erosion of inhibitory control over efforts to refrain from drug use, and
- compulsive drug taking (DSM-5).
These behavioral changes in turn are associated with structural and functional changes in the reward, inhibitory, and emotional circuits of the brain.
Clinical studies have also shown that the ability of opioids to produce addiction is genetically modulated, with heritability rates similar to those of diabetes, asthma, and hypertension.
For these reasons, we do not know the total dose or the duration of opioid administration that will reliably produce addiction.
However, we do know that the risk of opioid addiction varies substantially among persons, that genetic vulnerability accounts for at least 35 to 40% of the risk associated with addiction, and that adolescents are at increased risk because of the enhanced neuroplasticity of their brains and their underdeveloped frontal cortex, which is necessary for self-control. Hence, in adolescents, the risks and benefits of prescribing opioids for pain management need to be even more carefully weighed than in adults.
In a person with an opioid addiction, discontinuation of the opioid will rapidly reverse the tolerance and physical dependence within days or a couple of weeks. In contrast, the underlying changes that are associated with addiction will persist for months and even years after the discontinuation of opioids.
This finding is clinically relevant, because after abstinence from opioids, addicted patients are particularly vulnerable to overdosing: their intense drive to take the drug persists, but the tolerance that previously protected them from overdosing is no longer present. These effects explain the high risk of overdosing among persons with an opioid addiction after they have been released from prison or from a detoxification program.
The rewarding effects of opioids play a major role in the risks of opioid diversion, overdose, and addiction. However, the likelihood and severity of these risks are largely independent and governed by different factors.
All these risks are present to some degree with all opioids and with all pain diagnoses. This means that no single or simple change in prescribing behavior can be expected to alleviate all risks while properly managing pain.
Preventing Drug Diversion
The most common form of diversion is the transfer of opioid analgesics by patients who have received legitimately prescribed opioids to family members or friends who are usually trying to self-medicate a generic pain
Approximately 7 to 10% of diversion occurs among patients who feign pain to acquire prescribed opioids, usually with the goal of maintaining their addiction, and who will often attempt to acquire opioids from multiple physicians (doctor shopping).
Physicians have attempted to identify dissembling or addicted patients through screening instruments or through detection of so-called aberrant behaviors that are thought to be indicative of addiction
However, the most recent review of patient screening efforts showed no evidence that any scale or procedure was effective. Risks of diversion through doctor shopping are best mitigated by the full participation of all prescribers in Prescription Drug Monitoring Programs (PDMPs).
It is no longer possible to simply continue previous practices with respect to the management of chronic pain.
I agree, but for a different reason: we need better methods of pain control and until we have those, depriving patients of relief is unethical and cruel.
The associated risks of opioid diversion, overdose, and addiction demand change. Although there are no simple solutions, we recommend three practice and policy changes that can reduce abuse-related risks and improve the treatment of chronic pain.
Increased Use of Science-Supported Prescribing and Management Practices
The extended prescription of opioids (>8 weeks) for the treatment of chronic pain has questionable benefits for individual patients and presents substantial public health risks.
The risks of overdose and addiction from this prescribing practice — both among patients with chronic pain and the public at large — increase with higher doses (>100 MME), longer duration of prescribing, and perhaps the use of long-acting opioids.
These are all indications of chronic pain as well, so the blame for the “opioid crisis” is placed on people with these characteristics: pain patients.
Despite these facts, a Medicaid study showed that more than 50% of opioid prescriptions were for doses higher than 90 MME and for periods of more than 6 months.
This is an indication of how prevalent and intense chronic pain has become in our society.
Better results can be obtained by using the most contemporary guidelines for pain management.
Better results of what? Less addiction and more pain?
The increasing numbers of “contemporary guidelines” only encourage opioid restrictions.
“Alternative medicine” is only effective for mild pain and only affordable for the rich because it’s not covered by insurance.
All these guidelines offer no solutions for the chronic pain being suffered.
Increased Medical School Training on Pain and Addiction
Very few medical schools offer adequate training in pain management, and still fewer offer even one course in addiction.
The result is that even experienced clinicians are unsure about how to deal with fundamental and omnipresent clinical issues in their practices.
Many motivated, well-intentioned physicians do not know whether to prescribe opioids for pain management and, if so, which ones and for how long. Still fewer understand the pharmacologic or clinical relationships among tolerance, physical dependence, and addiction.
This education is particularly critical for primary care practitioners, who prescribe more than 70% of opioid analgesics.
Increased Research on Pain
At a recent workshop at the National Institutes of Health on the role of opioids in the treatment of chronic pain, attendants recommended several areas of research that are needed for improved clinical practice guidelines.
These areas included
- how to differentiate the unique properties of acute and chronic pain and
- how to describe the process by which acute pain transitions into chronic pain.
Discovery-oriented research was also recommended to identify new, potent nonopioid analgesics and other pain-treatment strategies
That’s great for the distant future, but what about people suffering constant intense pain NOW?
Access to biomarkers of pain and analgesia that take advantage of neuroimaging technologies or genetic analyses would accelerate the development of new medications and allow for more personalized clinical interventions for pain management.
Physicians hate it most when a patient complains of pain that cannot be measured because it means they can only take the patient’s word.
What does it say about the current practice of medicine that that physicians are so reluctant to believe what their patients say?